Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression
Abstract
:1. Introduction
2. Results
2.1. Clinical Description
2.2. Stromal and Immune Cell Infiltration Is Associated with Poor Prognosis in Uveal Melanoma (UM)
2.3. Combination of Angiogenesis and Antigen Presentation Confers Poor Prognosis
2.4. Metabolic and Tyrosine Kinase Pathways Are Activated in Poor-Prognosis Tumors
3. Discussion
4. Materials and Methods
4.1. Patients and Samples
4.2. Microenvironment Characterization
4.3. TMB (Tumor Mutational Burden)
4.4. Angiogenesis and Antigen Presentation Enrichment Analysis
4.5. Hierarchical Clustering
4.6. Functional Analysis
4.7. Statistical Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
aDC | activated dendritic cell |
Angio | Angiogenesis |
AP | Antigen Presentation |
B2M | Beta-2-Microglobulin |
BAP1 | BRCA1 Associated Protein 1 |
CALR | Calreticulin |
CI | Confidence Interval |
CM | Cutaneous Melanoma |
CTLA-4 | Cytotoxic T-Lymphocyte Antigen-4 |
D3 | Disomy of Chromosome 3 |
DC | dendritic cell |
DEG | Differentially Expressed Genes |
DFS | Disease Free Survival |
FPKM | Fragments per Kilobase per Million |
GEO | Gene Expression Omnibus |
GSEA | Gene Set Enrichment Analysis |
GSVA | Gene Set Variation Analysis |
GZMA | Granzyme A |
HLA | Human Leukocyte Antigen |
HR | Hazard Ratio |
iDC | immature dendritic cell |
IL2 | Interleukin-2 |
IPS | Immunophenoscore |
KM | Kaplan-Meier |
M1 | liver metastasis |
M1a | small lesion liver metastasis |
M3 | Monosomy of Chromosome 3 |
MSigDB | Molecular Signatures Database |
mTORC1 | Mammalian target of rapamycin complex 1 |
MUM | Metastatic Uveal Melanoma |
NES | Normalized Enrichment Score |
NK | Natural Killer |
OS | Overall Survival |
PD-1 | Programmed Cell death protein 1 |
PDL1 | Programmed Death Ligand 1 |
PET-TC | Positron emission tomography |
PFS | Progression Free Survival |
PI3K | Phosphoinositide 3-kinase |
PRF | Perforin |
TAP | Tapasin |
TIL | Tumor Infiltrating Lymphocyte |
TIS | T-cell Inflammatory Signature |
TMB | Tumor Mutational Burden |
TME | Tumor microenvironment |
TNF-α | Tumor Necrosis Factor alpha |
UM | Uveal Melanoma |
VEGF | Vascular Endothelial Growth Factor |
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Variable | Entire Cohort n = 213 | GSE22138 n = 63 | GSE27831 n = 29 | GSE73652 n = 13 | GSE84976 n = 28 | TCGA n = 80 | p-Value |
---|---|---|---|---|---|---|---|
Age | 62.3 | 61.0 | 66.0 | 61.6 | 62.2 | 0.411 | |
Sex | 0.801 | ||||||
Female | 71 (41.3%) | 24 (38.1%) | 12 (41.4%) | 0 (0.0%) | 0 (0.0%) | 35 (43.8%) | |
Male | 101 (58.7%) | 39 (61.9%) | 17 (58.6%) | 0 (0.0%) | 0 (0.00%) | 45 (56.2%) | |
NA | 41 | 0 (0.0%) | 0 (0.0%) | 13 (100%) | 28 (100%) | 0 (0.0%) | |
Chr 3 status | <0.001 | ||||||
Disomy | 64 (32.2%) | 18 (28.6%) | 11 (37.9%) | 0 (0.0%) | 14 (50.0%) | 21 (26.2%) | |
Partial monosomy | 5 (2.5%) | 5 (7.94%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
Monosomy | 94 (47.2%) | 32 (50.8%) | 17 (58.6%) | 0 (0.0%) | 14 (50.0%) | 31 (38.8%) | |
NA | 36 (18.1%) | 8 (12.7%) | 1 (3.5%) | 13 (100%) | 0 (0.0%) | 28 (35.0%) | |
Cell type | <0.001 | ||||||
Epithelioid | 40 (18.7%) | 21 (33.3%) | 6 (20.7%) | 0 (0.0%) | 0 (0.0%) | 13 (16.2%) | |
Mixed | 72 (33.8%) | 23 (36.5%) | 12 (41.4%) | 0 (0.0%) | 0 (0.0%) | 37 (46.2%) | |
Spindle | 39 (18.3%) | 0 (0.0%) | 9 (31%) | 0 (0.0%) | 0 (0.0%) | 30 (37.5%) | |
NA | 60 (28.2%) | 19 (30.2%) | 0 (0.0%) | 13 (100%) | 28 (100%) | 0 (0.0%) | |
Recurrence | 0.245 | ||||||
Non-recurrent | 119 (55.9%) | 28 (44.4%) | 18 (62.1%) | 8 (61.5%) | 15 (53.6%) | 50 (62.5%) | |
Recurrent | 94 (44.1%) | 35 (55.6%) | 11 (37.9%) | 5 (38.5%) | 13 (46.4%) | 30 (37.5%) | |
DFS Months | 38.6 | 41.1 | 37.2 | 77.8 | 23.2 | <0.001 |
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García-Mulero, S.; Alonso, M.H.; del Carpio, L.P.; Sanz-Pamplona, R.; Piulats, J.M. Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression. Int. J. Mol. Sci. 2021, 22, 2669. https://doi.org/10.3390/ijms22052669
García-Mulero S, Alonso MH, del Carpio LP, Sanz-Pamplona R, Piulats JM. Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression. International Journal of Molecular Sciences. 2021; 22(5):2669. https://doi.org/10.3390/ijms22052669
Chicago/Turabian StyleGarcía-Mulero, Sandra, Maria Henar Alonso, Luis P. del Carpio, Rebeca Sanz-Pamplona, and Josep M. Piulats. 2021. "Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression" International Journal of Molecular Sciences 22, no. 5: 2669. https://doi.org/10.3390/ijms22052669